The existence of the histamine H3 receptor has been known for several years and the receptor is of current interest for the development of new medicaments (see, for example, Drugs Fut 1996; 21: 507-20; Progress in Drug Research 1995; 45: 107-65). The human histamine H3 receptor has been cloned, cf. Molecular Pharmacology, 1999; 55: 1101-7. The histamine H3 receptor is a presynaptic autoreceptor located mainly in the central nervous system. Recent evidence suggests that the H3 receptor shows intrinsic, constitutive activity, in vitro as well as in vivo (i.e., it is active in the absence of an agonist; see, for example, Nature 2000; 408: 860-4). Compounds acting as inverse agonists can inhibit this activity. The histamine H3 receptor has been demonstrated to regulate the release of histamine and also of other neurotransmitters such as serotonin and acetylcholine. A histamine H3 receptor antagonist or inverse agonist would therefore be expected to increase the release of these neurotransmitters in the brain. A histamine H3 receptor agonist, on the contrary, leads to an inhibition of the biosynthesis of histamine and an inhibition of the release of histamine and also of other neurotransmitters such as serotonin and acetylcholine. These findings suggest that histamine H3 receptor agonists, inverse agonists and antagonists could be important mediators of neuronal activity. Accordingly, the histamine H3 receptor is an important target for new therapeutics.
Several publications disclose the preparation and use of histamine H3 agonists and antagonists. Some of these are imidazole derivatives (see, for example, Drugs Fut 1996; 21: 507-20; Expert Opinion on Therapeutic Patents 2000; 10: 1045-55). However, a variety of imidazole-free ligands of the histamine H3 receptor is also described (see, for example, Arch Pharm Pharm Med Chem 1999; 332: 389-98; J Med Chem 2000; 43: 2362-70; Arch Pharm Pharm Med Chem 1998; 331: 395-404; II Farmaco 1999; 54: 684-94; WO 99/42458, EP 0 978 512, WO 97/17345, U.S. Pat. No. 6,316,475, WO 01/66534, WO 01/74810, WO 01/44191, WO 01/74815, WO 01/74773, WO 01/74813, WO 01/74814 and WO 02/12190. The state of the art is also reviewed in Drug Discovery Today, 2005; 10: 1613-17; Nat Rev Drug Discov, 2005; 4: 107, and Drug Dev Res, 2006, 67: 651-665. In view of the art's interest in histamine H3 receptor agonists, inverse agonists and antagonists, novel compounds which interact with the histamine H3 receptor would be a highly desirable contribution to the art.
In WO 03/066604, 3-(4-cyclopropylpiperazin-1-yl)-6-(3,4-dimethoxyphenyl)pyridazine hydrochloride is mentioned in Example 127.